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Intratumoural administration and tumour tissue targeting of cancer immunotherapies

Nature Reviews Clinical Oncology volume 18, pages 558–576 (2021)Cite this article

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Abstract

Immune-checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are revolutionizing oncology and haematology practice. With these and other immunotherapies, however, systemic biodistribution raises safety issues, potentially requiring the use of suboptimal doses or even precluding their clinical development. Delivering or attracting immune cells or immunomodulatory factors directly to the tumour and/or draining lymph nodes might overcome these problems. Hence, intratumoural delivery and tumour tissue-targeted compounds are attractive options to increase the in situ bioavailability and, thus, the efficacy of immunotherapies. In mouse models, intratumoural administration of immunostimulatory monoclonal antibodies, pattern recognition receptor agonists, genetically engineered viruses, bacteria, cytokines or immune cells can exert powerful effects not only against the injected tumours but also often against uninjected lesions (abscopal or anenestic effects). Alternatively, or additionally, biotechnology strategies are being used to achieve higher functional concentrations of immune mediators in tumour tissues, either by targeting locally overexpressed moieties or engineering ‘unmaskable’ agents to be activated by elements enriched within tumour tissues. Clinical trials evaluating these strategies are ongoing, but their development faces issues relating to the administration methodology, pharmacokinetic parameters, pharmacodynamic end points, and immunobiological and clinical response assessments. Herein, we discuss these approaches in the context of their historical development and describe the current landscape of intratumoural or tumour tissue-targeted immunotherapies.

Key points

  • Repeated intratumoural injections with agents designed to enhance antitumour immune responses constitutes a feasible strategy to reduce the risk of systemic toxicities and achieve higher local bioactive drug concentrations.

  • Spearheaded by the oncolytic virus talimogene laheparepvec, the first intratumoural immunotherapy approved by the FDA and EMA, and supported by a strong preclinical rationale, many intratumoural immunotherapies are now being developed in clinical trials.

  • These immunotherapies include microorganisms (viruses or bacteria) and synthetic compounds mimicking infectious agents (such as pattern recognition receptor agonists), as well as immunomodulatory monoclonal antibodies, cytokines and chimeric proteins.

  • Higher locoregional concentrations of immunotherapy agents can also be achieved through molecular engineering, for example, to target them towards moieties that are enriched in the tumour microenvironment.

  • Increased specificity in tumour targeting can also be attained through the development of prodrug forms of immunotherapies that become functional only after entering tumour tissue (pro-immunodrugs).

  • Procedural, pharmaceutical, regulatory and analytical challenges require multidisciplinary expert consensus and systematic research to maximize the potential of these modes of administration.

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Fig. 1: Strengths, weaknesses, opportunities and threats of intratumoural delivery of immunotherapies.
Fig. 2: Current landscape of active clinical trials of intratumoural immunotherapies.
Fig. 3: Boosting the intratumoural cancer immunity cycle.
Fig. 4: Targeted approaches to immunotherapy against solid tumours.

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Acknowledgements

The authors thank the patients, the patients’ families and colleagues who have participated in the authors’ preclinical and clinical research projects on intratumoural immunotherapy and have contributed to the development of the authors’ expertise in that field. The authors thank in particular T. de Baere, L. Tselikas, S. Ammari, S. Farhane and C. Massard for their contribution to the implementation of intratumoural immunotherapy trials at Gustave Roussy. The authors also thank their colleagues at the University of Navarra, especially A. Benito, M. Rodriguez-Ruiz, M.F. Sanmamed, C. de Andrea, J.L. Perez-Gracia, M. Ponz, L. Resano, I. Goicoechea and M. Egaña. The work of M.A. is funded by the Asociación Española contra el Cancer (AECC) Foundation, and the authors acknowledge continued financial support from the Spanish Ministry of Economy and Competitiveness (MINECO SAF2014-52361-R and SAF 2017-83267-C2-1R (AEI/FEDER,UE)), the Cancer Research Institute under the CRI-CLIP, the AECC Foundation under grant GCB15152947MELE, the Joint Translational Call for Proposals 2015 (JTC 2015) TRANSCAN-2 (code TRS715 2016-00000371), and the European Commission within the Horizon 2020 Programme (PROCROP - 718 635122).

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Authors and Affiliations

  1. Department of Immunology, Clínica Universidad de Navarra, Pamplona, Spain

    Ignacio Melero & Eduardo Castanon

  2. Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain

    Ignacio Melero & Eduardo Castanon

  3. Program for Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Universidad de Navarra, Pamplona, Spain

    Ignacio Melero & Maite Alvarez

  4. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain

    Ignacio Melero & Maite Alvarez

  5. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

    Ignacio Melero & Maite Alvarez

  6. Département d’Innovation Thérapeutique et d’Essais Précoces (DITEP), Université Paris Saclay, Gustave Roussy, Villejuif, France

    Stephane Champiat & Aurelien Marabelle

  7. INSERM U1015, Gustave Roussy, Villejuif, France

    Stephane Champiat & Aurelien Marabelle

  8. Biotherapies for In Situ Antitumor Immunization (BIOTHERIS), Centre d’Investigation Clinique INSERM CICBT1428, Villejuif, France

    Stephane Champiat & Aurelien Marabelle

Authors
  1. Ignacio Melero
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  2. Eduardo Castanon
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  3. Maite Alvarez
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  4. Stephane Champiat
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  5. Aurelien Marabelle
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Ignacio Melero or Aurelien Marabelle.

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Competing interests

I.M. has received research grants from Alligator, Bioncotech, Bristol Myers Squibb (BMS), Leadartis, Pfizer and Roche; has received speaker’s bureau honoraria from MSD; and is a consultant or advisory board member for Alligator, AstraZeneca, Bayer, Bioncotech, BMS, F-Star, Genmab, Gossamer, Merck Serono, Numab, Pieris and Roche. E.C. is a consultant or advisory board member for AstraZeneca, Beigene, BMS, MSD and Roche. S.C. has received honoraria from Amgen, AstraZeneca, BMS, Janssen, Merck, MSD, Novartis and Roche; is an advisory board member for Amgen and AstraZeneca; has received funding for travel and conference attendance from AstraZeneca, MSD and Roche; and has received research grants from AstraZeneca, BMS, Boehringer Ingelheim, Janssen-Cilag, Merck, Novartis, Onxeo, Pfizer, Roche and Sanofi, and non-financial research support (investigational drugs) from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Medimmune, Merck, NH TherAGuiX, Onxeo, Pfizer and Roche. S.C. has been a principal investigator of academic or industry-sponsored clinical trials of intratumoural immunotherapies for Abbvie, AstraZeneca/Medimmune, BMS, Eisai/H3 Biomedicine, IDERA, Lytix Biopharma, MSD, Nanobiotix and Sanofi/BioNTech. A.M. has been a principal investigator of academic or industry-sponsored clinical trials of intratumoural immunotherapies from AstraZeneca, BMS, Eisai, IDERA, Lytix Biopharma, Merck/MSD, Roche and Transgene; is a member of the Data Safety and Monitoring Board of a trial of a intratumoural TLR3 agonist sponsored by Oncovir (NCT02423863); and has participated in scientific advisory boards or has provided consultancy services on the topic of intratumoural immunotherapies for Amgen, AstraZeneca, Banque Pour l’Investissement, Bayer, Eisai, eTheRNA, Lytix Biopharma, Medincell, MSD, Novartis, Oncosec, Pillar Partners, Rigontec and Sanofi/BioNTech. M.A. declares no competing interests.

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Melero, I., Castanon, E., Alvarez, M. et al. Intratumoural administration and tumour tissue targeting of cancer immunotherapies. Nat Rev Clin Oncol 18, 558–576 (2021). https://doi.org/10.1038/s41571-021-00507-y

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